The aim of the proposed renewal project is to further our understanding of the role of hemodynamics in atherogenesis; in particular to elucidate mechanisms by which hemodynam ic/biomechanical forces modulate the transcytotic and cellular responses of the vessel wall. A multidisciplinary research team has joined forces in an integrated approach to accomplish our stated aims. Our research plan is built around a novel and reliable in vitro pulsatile perfusion apparatus which exposes freshly excised animal and human vessels (arteries and veins) to well-defined hemodynamics. An important feature of this device is that hemodynamic parameters (e.g., intraluminal pressure, transmural pressure, pulse pressure, rate of flow, etc.) can be individually varied and the biologic/biomechanical response of the vessel wall studied in detail. It is our hypothesis that the de- livery of defined, realistic hemodynamics in vitro provides an environment in which we are able to study, on a fundamental level, how hemodynamic forces influence molecular and cellular aspects of the disease process. Specific timely questions that our studies will address include: i) why vein grafts may "fail" when sewn into the arterial circulation; in particular which arterial hemodynamic parameter(s) modulate the normal metabolic and cellular response of veins; ii) how cellular metabolism, structure and function are influenced by "high" versus "low" shear stress; iii) whether cytoskeletal adaptation to hemodynamic/biomechanical forces contributes to the characteristicallyfocal nature of atherogenesis in vivo; iv) if hemodynamics initiate extracellular matrix reorganization by altering arterial wall metabolism; v) if hemodynamics (e.g., hypertension) accererates lipid accumulation and cellular metabolism at or adjacent to sites of plaque versus lesion free areas; vi) which cell types are most active in LDL degradation in atherosclerotic and non-atherosclerotic portions of human arteries perfused in vitro and which receptors, if any, are involved in this cellular uptake; and, vii) whether "disease susceptible" versus "disease resistant" arteries differ as a function of the aforementioned parameters in response to hemodynamics. To our best knowledge, this integrated approach in which we systematically vary individual hemodynamic parameters and measure the biologic response of the vessel wall to these hemodynamic variables, is unavailable in other bioengineering protocols and marks s important advance toward understanding the role of hemodynamics an atherogenesis.